A critical feature of the immune system is its ability to distinguish between self and nonself: seemingly ignorm self antigens while responding to and eliminating potential pathogens. Failure of this discrimination can result autoimmuniry. While, auto-reactive antigen receptors are clearly encoded in the genome, cells expressing the receptors are silenced by a variety of mechanisms. In the B cell compartment this occurs by antigen induce^ editing of receptors to change specificity, deletion by apoptosis, anergy and CDS dependent hyporesponsiveness.| In the latter two cases, cells remain viable and competent to bind antigen, but antigen receptor signaling is altered. The long-term objectives of the application are to elucidate the molecular mechanisms underlying the antige hyporesponsiveness of anergic B cells and peritoneal CD5+ cells. Specific Aims are to elucidate the biochemic underpinning and biological functions of three specific mechanisms of signal modulation revealed by studie: conducted during the last funding period. Two of these mechanisms, active in anergic B cells, involve(1)1 destabilization of the antigen receptor preventing normal transmission of signals from membrane immunoglobulin| to Ig-o/Ig-p dimers which function as the receptor's transmembrane transducer, and (2) activation of a negativi feedback regulatory loop involving the inositol 5 phosphatase SHIP and the linker Downstream of kinase, Dok. third mechanism, apparently operative only in peritoneal CD5+ cells, is an inhibitory loop involving Lck, CDS an SHP-2 and targets BLNK (SLP-65). The proposed studies will be pursued using multiple lymphoma and animal models, but will rely principally on the newly described Ars/Al trangenic model of anergy and the VH11VK9 transgenic model of CD5+ Bl cells. They will involve genetic manipulation and a variety of biochemical and biological assays of signal transduction and cellular responses. These studies may reveal drug discovery targets for autoimmunity and immunodeficiency.